Anorexia nervosa--a noradrenergic dysregulation hypothesis.

Anorexia nervosa manifests a wide range of features which cannot fully be explained on the basis of socio-cultural pressures to be thin, nor by starvation, nor dehydration. Evidence is emerging of a significant neurobiological contribution to its aetiology. However there has to date been no explanation for its pathogenesis that integrates the previously identified genetic, neurobiological and socio-cultural contributing factors. In this paper we propose an empirically-based hypothesis that genetically determined noradrenergic dysregulation, interacting with epigenetic factors, leads to high levels of anxiety, impaired neuroplasticity and regional cerebral hypoperfusion. These, in combination, lead to insula dysfunction. The resulting impairment in insula homuncular representation explains the pathognomonic body image distortion. This distortion, combined with high levels of body-focused anxiety, gives rise to intense dieting, noradrenergic precursor depletion, and initial reduction in anxiety. The subsequent rebound exacerbation of anxiety leads to a vicious cycle of maintenance. Novel treatment implications based on this hypothesis are briefly considered.

Anorexia nervosa and the insula.

Anorexia nervosa is a serious illness with major physical and psychological morbidity. It has largely been understood in terms of cultural and environmental explanations. However these are insufficient to explain the diverse clinical features of the illness, nor its rarity given the universality of sociocultural factors. Over the last 20 years, there has been a steady accumulation of neurobiological evidence requiring a re-formulation of current causal models. We now offer a new empirically-derived hypothesis implicating underlying rate-limiting dysfunction of insula cortex as a crucial risk factor for the development of anorexia nervosa. Supporting evidence for this hypothesis is drawn from anatomical and clinical research of insula cortex damage in humans and neuroscientific studies of relevant clinical features including taste, pain perception and reward processing. This hypothesis, if sustainable, would be the first fully to explain the disorder and predicts promising novel treatment possibilities including Cognitive Remediation and Motivation Enhancement Therapies. The knowledge that the challenging behaviours, so characteristic of AN, are the result of underlying cerebral dysfunction, rather than being purely volitional, could help to reduce the stigma patients experience and improve the therapeutic alliance in this poorly understood and difficult to treat disorder.

The fault is not in her parents but in her insula--a neurobiological hypothesis of anorexia nervosa.

The reported abnormalities of brain function in anorexia nervosa (AN) include impairment of neural circuits involving cortical (orbito-frontal, somatosensory and parietal) and sub-cortical (amygdala, hippocampus, thalamus, hypothalamus and striatum) structures. The insular cortex serves an integrative function for all the structures relevant to the features of AN and as such may be central to this impairment. We hypothesise that a rate limiting dysfunction of neural circuitry integrated by the insula can account for the clinical phenomena of AN. Such dysfunction could account for the known psychopathology, neuroimaging abnormalities and neuropsychological deficits. Proposals to test this hypothesis are made.